Alkaline bismuth tartrate solution



Patented Apr. 21, 1931 UNITED STATES PATENT OFFICE PHILIP ADOLPE KOBER, F EVANSTON, ILLINOIS, ASSIGNOR TO G. D. SEARLE & CO., OF CHICAGO, ILLINOIS, A CORPORATION OF ILLINOIS ALKALINE BISMUTH TARTRATE SOLUTION No Drawing. Application filed Kay 1,

This invention relates to the preparation of aseptic solutions for subcutaneous injection, and more particularly to the preparation of solutions of alkali metal bismuth tartrates adapted for intramuscular injection.

The use of bismuth com ounds in the treatment of syphilis is of considerable importance and an improved process for the manufacture of alkali metal bismuth tartrates is described in my Patent No. 1,663,201, issued March 20, 1928. p

It is an object of the present invention to provide a process for dissolving and holding in solution tartrates of bismuth and in particular tetra bismuth tartrates.

A further object is to prepare a' solution of alkali metal bismuth tartrates and a local anesthetic so selected that'there will be no chemical action between the components of roduction of reaction uble or otherwlse unthe solution with the products that are inso desirable.

Sometimes aqueous solutions of the usual bismuth tartrates are administered intraveotherwise alter the'bismuth preparation.

These conditions have been so difiicult to fulfil, especially the third, that most bismuth preparations are put up as suspensions in 011,

which makes the absorption of the bismuth undesirably slow.

Now, I have been able to prepare, and it is a fu'rther object of the invention to provide a solution of alkali metal bismuth tartrates which, after thousands of experiments, has

1928. Serial No. 274,350.

been proven to possess all four of the above mentioned characteristics.

I have discovered that strong, that is, hypertonic solutions of cane sugar or sucrose are not onlycompatible with alkali bismuth tartrates, but that these solutions render the tartrate more stable and less irritating and damaging to the muscular tissues.

Isotonic solutions (about 5%) of sugars have been used for menstrua of metallic bismuth suspensions and a few alkali metal bismuth tartrates of low bismuth content or less) in order to make the solution isotonic to blood; but apparently its protective or bufier action was not known or recognized, for to get complete bufi'er ac-" tion these solutions are not strong enough; 20 to 50% solutions are required for. this stabilization. Bythe word"bufl"er it is to be understood that I refer to the general stabilizing and solvent effects of the sugar, which makes the tartrate less likely to precipitate upon contact with the blood.

Other sugars than sucrose, such for exam ple as glucose, may be similarly employed, but, while my invention contemplates the use of any sugar in hypertonic solution, my preferred form of the invention embraces sucrose.

While this action of the sugars makes the injection intramuscularly easily tolerated by the patient, it also makes its administration safer intravenously, as it makes the bismuth compound less active chemically until it has been generally distributed throughout the body and metabolized.

In addition to make the alkali metal bismuth tartrate stable in solution and non-irritating or damaging to the tissues, it was necessary to find a local anesthetic to alleviate.

the pain of injection into the muscular tissue. In selectin an anesthetic, it is of course necessary to d one which is first, soluble in water or the menstruum employed; and second, one which will not react with the other substances present to form reaction products that are insoluble or otherwise objectionable. Many local anesthetics were tried; many are so insoluble in water that they serve no useful purpose; others have acid groups attached which I found reacted with the alkali metal bismuth tartrates on standing to form insoluble gelatinous precipitates, making the product obviously unsuitable for injection.

After much experimentation, benzyl alcohol was found to be a suitable local anesthetic, being soluble and having no action on long standing upon the alkali metal tartrates. Procaine hydrochloride was also found useful as a local anesthetic for these alkali metal bismuth tartrate preparations as the following illustration shows. To an aqueous solu tion of alkali metal tartrate, for example, sodium bismuth tartrate, was added 1% p rocaine hydrochloride crystals; on dissolving the crystals precipitated the bismuth compound; but in making the solution hypertonic with sugar, the precipitate dissolves to a perfectly clear solution, which shows the useful protective and stabilizing action of the sugar.

Other local anesthetics may be found or developed for fulfilling the requirements of this purpose, in that they are soluble and do not react with alkali metal tartrates, without deviating from the spirit of the present invention. i

In practice I prefer making such a solution for intramuscular and other administrations as follows:

75 grams of alkali metal bismuth tartrate, preferably sodium bismuth tartrate, are dissolved in 7 cc. of water to which is added 1250 gm. of sucrose dissolved in 3000 cc. of

- distilled water. After shaking and mixing,

100 cc. of benzyl alcohol are added and the solution again throughly shaken until all of the benzyl alcohol is dissolved. The solution is then diluted to a volume of 5000 cc. with distilled water, and is then filtered with the aid of alittle tale. The solution is then siphoned oil' into ampoules which are hermetically sealed, or into other vessels such as vials suitable for sterilizing and that keep the solutions sterile. After sterilization the solutions are ready for injection.

I claim:

1. An aqueous hypertonic sugar solution containing alkali metal bismuth tartrate,

1 said solution being compatible with blood,

and sufiiciently stable to permit absorption and general distribution in the body before substantial alteration of said solution takes place.

2. An aqueous hypertonic sugar solution containing alkali metal bismuth tartrate and benzyl alcohol, said solution being compati ble with blood, substantially painless on injection, and sufiiciently stable to permit absorption and general distribution in the body before substantial alteration takes place.

3. An aqueous hypertonic sugar solution containing alkali metal tetra bismuth tartrate, said solution being compatible with blood, and sufficiently stable to permit absorption and general distribution in the body before substantial alteration of said solution takes place.

4. An aqueous hypertonic sugar solution containing alkali metal bismuth tartrate and one of the group comprising benzyl alcohol and procaine hydrochloride, said solution bemg compatible with blood, substantially painless on injection, and sufficiently stable to permit absorption and general distribu tion in the body before substantial alteration takes place.

An aqueous hypertonic sugar solution made with sucrose and containing sodium bismuth tartrate, said solution being compatible with blood, and sutliciently stable to permit absorption and general distribution in the body before substantial alteration of said solution takes place.

PHILIP ADOLPH KOBER. 

